Targeting lactate transport suppresses in vivo breast tumour growth.

BACKGROUND Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as "Warburg effect". Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment. RESULTS The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth. CONCLUSIONS This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of in vivo breast tumour growth by targeting lactate transport.

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) (grant number PTDC/ SAU-FCF/104347/2008), under the scope of “Programa Operacional Temático Factores de Competitividade” (COMPETE) of “Quadro Comunitário de Apoio III” and co-financed by the Fundo Europeu De Desenvolvimento Regional (FEDER). FM-S, VM-G and AHJM received doctoral fellowships from FCT (refs. SFRH/BD/87139/2012, SFRH/BD/ 51997/2012 and SFRH/ BD/68270/2010, respectively). SG received a postdoctoral fellowship from UMINHO/BPD/18/2014 and CP from FCT (ref. SFRH/BPD/69479/2010).